The present invention concerns methods of screening for risk of, or predisposition to, pancreatic cancer.
Cancer of the pancreas is an important cause of cancer mortality in developed countries and accounts for more than 28,000 deaths in the U.S. per year. Pancreatic cancer produces few specific symptoms in its early stages and usually is detected at an advanced and incurable stage. This contributes to pancreatic cancer having the worst survival of any major cancer; the average survival after diagnosis is less than 6 months and fewer than 5% of patients survive 5 years (Rosenberg, L. (1997) Pancreatol. 22:81-93; Flanders and Foulkes (1996) J. Med. Genet. 33:889-898).
The etiology of pancreatic cancer is obscure (see refs Anderson, et al. (1996) In D. Schottenfeld, J. F. Fraumeni, J. F., Jr. Cancer Epidemiology and Prevention, 2nd Ed., Oxford University Press, New York, pp. 725-771; Fontham and Correa (1989) Surg. Clin. North Am. 69:551-567; Fryzek, et al. (1997) GI Cancer 2:99-100 for reviews of the epidemiology). Incidence rates for pancreatic cancer increase exponentially with age beginning at about age 40, are approximately 50% higher among males than females, and are higher among blacks than whites. Despite considerable epidemiologic study, the only modifiable risk factor that has been established is cigarette smoking. However, the identity of the carcinogen(s) in cigarette smoke is unknown. Few strong occupational risks have been detected, although moderate risks have been associated with several industries, including metal working occupations and pesticide exposure (Pietri and Clavel (1991) Br. J. Ind. Med. 48:583-587). Mapping of U.S. mortality rates from pancreatic cancer has identified significantly elevated rates in southern Louisiana (Blot, et al. (1978) Cancer 42:373-380), but the cause of that cluster remains largely unexplained.
Toxicological properties of cadmium. Cadmium, atomic number 48, is a soft, silver-white metal that is found naturally at low levels in rocks and soil. Cadmium is used in a variety of industries, e.g., in nickel-cadmium batteries, electroplating, as a component in metallurgical and brazing-soldering alloys, in pigments, and as a stabilizer for plastic. Most of the cadmium produced in the U.S. is extracted during the smelting of other metals, such as zinc, lead, or copper. Smelters are a major source of airborne cadmium contamination. Other sources of environmental cadmium are the burning of fossil fuels and waste materials, and the use of phosphate fertilizers and sewage sludge (I.A.R.C. IARC Monographs on the evaluation of carcinogenic risks to humans. Vol. 58. Beryllium, cadmium, mercury and exposures in the glass manufacturing industry. IARC, Lyon, France; Yost, K. J. (1979) Hlth. Persp. 28:5-16; Cabrera, et al. (1998) Rev.Environ. Contam. Toxicol. 154:55-81; Davis, R. D. Cadmium in sludges used as fertilizer. Experientia Suppl., 50:55-65, 1986).
Cadmium that is present in soil as the result of industrial emissions or fertilization can be taken up selectively by edible plants, producing cadmium concentrations many times that of the surrounding soil (Korzun and Heck (1990) J. Air Waste Manage. Assoc. 40:1220-1226). Similarly, many water plants biomagnify the levels of cadmium in the surrounding water. Cadmium levels in fish, especially Mollusca and Crustacea (e.g., oysters, shrimp, crab and crayfish), can be greatly elevated (Noqvi, et al. (1993) J. Environ. Sci. Hlth. B 28:473-485). Most of the cadmium in crustaceans is contained within a single organ, the hepatopancreas (Jorhem, et al. (1994) Arch. Environ. Contam. Toxicol. 26:137-142; White and Rainbow (1986) Com. Biochem. Physiol. C 13:111-116; Engel, D. W. (1983) Science Total Environ. 28:129-140), which is commonly consumed by humans. For example, plants grown for 7 days in 0.00224 parts per billion (ppb) cadmium were fed to Louisiana red swamp crayfish (Procambarus clarkii) for 14 days. Accumulation of cadmium in hepatopancreata increased from 176.8 ppb on day 0 to 4,657.6 ppb on day 14 (Devi, et al. (1996) Ecotoxicol. Environ. Safety 33:38-43). Cadmium levels in edible crab (Cancer pagurus) may be as high as 30-50 parts per million (Overnell J. (1996) Environ. Health Perspect. 65:101-105). Consumption of one crab meal per week has been estimated to exceed the WHO provisionally tolerable cadmium intake of less than 500 xcexcg (Lind, et al. (1995) Food Chem.Toxicol. 33:667-673; World Health Organization. Toxicological Evaluation of Certain Food Additives and Contaminants. WHO Food Additive Series 24, World Health Organization, Geneva, 1989).
Food is the main source of cadmium for the non-smoking population. Estimates of dietary cadmium intake worldwide range from 10 to 40 xcexcg/day in nonpolluted areas to several hundreds of micrograms in cadmium-polluted regions. In the U.S., the average person consumes approximately 30 xcexcg cadmium per day in food and absorbs 1-3 xcexcg from the gastrointestinal tract. Smoking is an important source of cadmium exposure (Jarop, et al. (1998) Scand. J. Work Environ. Health 24: Suppl 1:1-51). One cigarette contains approximately 1-2 xcexcg cadmium, and smokers absorb an additional 1-3 xcexcg cadmium/day from the respiratory tract (Agency for Toxic Substances and Disease Registry. Toxicological profile for cadmium, April 1993 update. U.S. Publ. HIth. Serv.).
Most of the cadmium in the body is bound to metallothioneins, low molecular weight proteins that function in the homeostasis of essential metals, e.g., zinc (Hamer, D. H. (1986) Annu. Rev. Biochem. 55:913-951; De Lisle, et al. (1996) Am. J. Physiol. 271:C2204-1110). The cadmium-metallothionein complex is distributed to various tissues and organs and ultimately is reabsorbed in kidney tubuli Ohta and Cherian (1991) Toxicol. Appl. Pharmacol. 107:63-72). Because the body has no mechanism for the excretion of cadmium, cadmium accumulates in tissues. The half-life of cadmium in kidney cortex is 10-30 years. In humans, the largest amount of cadmium is deposited in the kidneys and liver, followed by the pancreas and lungs.
In 1993, The International Agency for Research on Cancer (IARC) classified cadmium and cadmium compounds as known human carcinogens (i.e., category 1 compounds) (Boffetta, P. (1993) Scand. J. Work Environ. Health 19:67-70). The most convincing human data implicate cadmium as a carcinogen in the lung, with equivocal evidence at other sites (e.g., prostate (Potts, C. L. (1965) Ann. Occup. Hyg. 8:55-61) and kidney (Kolonel, L. N. (1976) Cancer 37:1782-1787)).
The present invention is based on the recognition that elevated body levels of cadmium in a subject is a risk factor for pancreatic cancer. Greater levels of cadmium in the body indicate greater susceptibility to pancreatic cancer.
To our knowledge, this is the first report to propose that cadmium is a cause of human pancreatic cancer.
Accordingly, the present invention provides a method of screening for risk of pancreatic cancer in a subject, comprising detecting the presence or absence of increased levels of cadmium in the subject, with the presence of increased levels of cadmium in the subject indicating the subject is at increased risk of pancreatic cancer.
The present invention is explained in greater detail in the specification set forth below.
The present invention is primarily intended for human subjects, but may be carried out on animal subjects, particularly mammalian subjects such as cows, horses, pigs, sheep, goats, dogs, rats, mice, rabbits and the like for veterinary medicine purposes or drug screening and control purposes.
The present invention can be carried out with any human subject, including adult, adolescent and juvenile subjects; male and female subjects, and subjects of any race.
By screening for increased risk herein is meant detecting an increased risk of susceptibility or increased susceptibility to pancreatic cancer. Thus the present invention is intended primarily for prognostic purposes, although the invention may also be used for diagnostic purposes to confirm a suspected diagnosis of pancreatic cancer.
As noted above, the present invention provides a method of screening for risk of pancreatic cancer in a subject, comprising detecting the presence or absence of increased levels of cadmium in the subject, with the presence of increased levels of cadmium in the subject indicating the subject is at increased risk of pancreatic cancer. Where increased levels of cadmium are detected, those increased levels and/or the increased risk the step of providing a report of said increased risk of pancreatic cancer (i.e., to the subject, or in the case of a non-human subject such as a farm animal to the owner of the subject). The present invention is particularly usefuil in encouraging early intervention with the subject. Thus, if increased levels of cadmium are detected and increased risk is detected, any of a variety of interventions may be prescribed. These include:
(a) prescribing a dietary, occupational, or lifestyle change to decrease the intake of cadmium by said subject, and/or decrease other risk factors for pancreatic cancer (e.g., avoiding occupational exposure to cadmium, avoiding smoking, avoiding food sources containing greater quantities of cadmium, etc.;
(b) prescribing an increased monitoring of said subject for pancreatic cancer (which may be carried out in accordance with known techniques), or
(c) both (a) and (b) above.
The step of detecting cadmium levels may be carried out by any suitable technique. Numerous such techniques are known. Cadmium may be detected in a urine or serum sample collected from the subject, or may be detected in a tissue sample such as blood, hair, liver, kidney, or pancreas collected from the subject. By xe2x80x9cincreased levelsxe2x80x9d of cadmium in the subject is meant an increase in cadmium above, or substantially above, the average cadmium concentration in the general population for the given tissue or sample collected.